New Findings Could Potentially Lead to Novel Approaches to Treat Deadly Staph Infections
Newswise — A new study by NYU School of Medicine researchers suggests that an existing HIV drug called maraviroc could be a potential therapy for Staphylococcus aureus, a notorious and deadly pathogen linked to hundreds of thousands of hospitalizations each year. Their study is published online this week in Nature.
“What are the chances that a drug for HIV could possibly treat a virulent Staph infection?” asks Victor J. Torres, PhD, assistant professor of microbiology, and senior author of the study. “These findings are the result of a fantastic collaboration that we hope will result in significant clinical benefit.” Staph causes toxic shock syndrome, pneumonia, and food poisoning, among other illnesses, and is becoming increasingly resistant to antibiotics.
The discovery arose from a serendipitous finding that was a part of a collaborative study between Dr. Torres, a bacteriologist, and immunologist Derya Unutmaz, MD, associate professor of microbiology and pathology and medicine, whose laboratories are adjacent to each other.
They focused on a receptor called CCR5 that dots the surface of immune T cells, macrophages, and dendritic cells. Sixteen years ago, researchers at NYU School of Medicine discovered that CCR5 is the receptor HIV uses to gain entry into T cells in order to replicate, spread, and cause an infection that can progress into AIDS.
That same receptor has now been found to be critical to the ability of certain strains of Staph to specifically target and kill cells with CCR5, which orchestrate an immune response against the bacteria. The scientists discovered that one of the toxins the bacterium releases, called LukED, latches on to CCR5 and subsequently punches holes through the membrane of immune cells, causing them to rapidly die. The LukED toxin belongs to a family of proteins called leukotoxins, encoded and produced by Staph to fight off the immune system’s defenses.
This discovery was made after Dr. Torres asked Dr. Unutmaz and fellow HIV researcher Nathaniel Landau, PhD, professor of microbiology, if he might use some of the human immune cells they had collected over the course of their HIV studies. The laboratories of all three scientists are adjacent to each other. Dr. Torres was trying to find out which immune cells were affected by different leukotoxins. Dr. Unutmaz gave him a T cell line, which they were using for their HIV infection studies and had previously engineered to express CCR5, to test the effects of these toxins.
“Within one hour flat, T cells with CCR5 all died when exposed to LukED” says Dr. Torres, whereas a similar T cell line that lacked the receptor was completely resistant to the toxin’s effects. This observation quickly led to another set of experiments to determine that the LukED toxin was indeed interacting with the receptor and that its presence on the cell surface was necessary for the toxin to kill the cells.
The investigators then treated cells with CCR5 with maraviroc, a drug on the market that binds to CCR5 and blocks HIV infection, and then exposed the cells to the Staph toxin. The result, the scientists say, was astonishing. “It was remarkable. Maraviroc completely blocked the toxic effects of this leukotoxin at doses similar to those used to inhibit HIV infection” Dr. Unutmaz says.
“The goal in blocking the toxin with maraviroc or similar agents is to give the upper hand to the immune system to better control the infection,” Dr. Torres adds. The researchers further corroborated the critical role of CCR5 in Staph infections using a mouse model. When they infected mice susceptible to Staph infection with strains that contain the LukED toxin, almost all the mice died. However, mice that were genetically engineered to lack CCR5 on their cells survived this lethal Staph infection.
Based on these findings, the investigators hope that future human clinical trials will determine whether drugs that block CCR5, such as maraviroc, could help the immune system to control the infection and potentially save lives.
Other NYU School of Medicine researchers contributing to the study are Francis Alonzo III, PhD, Lina Kozhaya, Stephen A. Rawlings, Tamara Reyes-Robles, Ashley L. DuMont, and David G. Myszka, PhD.
The study was funded by grants from the National Institutes of Health, the NYU School of Medicine Development Funds, and an American Heart Association Scientist Development Grant.
About NYU School of Medicine
NYU School of Medicine is one of the nation’s preeminent academic institutions dedicated to achieving medical education excellence. For 170 years, NYU School of Medicine has trained thousands of physicians and scientists who have helped to shape the course of medical history and enrich the lives of countless people. An integral part of NYU Langone Medical Center, the School of Medicine at its core is committed to improving the human condition through medical education, scientific research and direct patient care. The School also maintains academic affiliations with area hospitals, including Bellevue Hospital, one of the nation’s finest municipal hospitals where its students, residents and faculty provide clinical and emergency care to New York City’s diverse population, which enhances the scope and quality of their medical education and training. Additional information about the NYU School of Medicine is available at http://school.med.nyu.edu/.
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NYU Langone Medical Center, a world-class, patient-centered, integrated, academic medical center, is one of the nation’s premier centers for excellence in clinical care, biomedical research and medical education. Located in the heart of Manhattan, NYU Langone is composed of four hospitals – Tisch Hospital, its flagship acute care facility; the Hospital for Joint Diseases, one of only five hospitals in the nation dedicated to orthopaedics and rheumatology; Hassenfeld Pediatric Center, a comprehensive pediatric hospital supporting a full array of children’s health services; and the Rusk Institute of Rehabilitation Medicine, the world’s first university-affiliated facility devoted entirely to rehabilitation medicine– plus NYU School of Medicine, which since 1841 has trained thousands of physicians and scientists who have helped to shape the course of medical history. The medical center’s tri-fold mission to serve, teach and discover is achieved 365 days a year through the seamless integration of a culture devoted to excellence in patient care, education and research. For more information, go to www.NYULMC.org.